Male circumcision has been shown to protect men from acquiring H.I.V. infection during sex with women  it has reduced female-to-male transmission rates by 48% to 60% in sub-Saharan Africa  but that protective effect appears less reliable among men who have sex with men, according to a new meta-analysis published Oct. 7 in the Journal of the American Medical Association (J.A.M.A.).

The review is the most comprehensive analysis of the subject to date. It encompasses data from 15 studies conducted in seven countries, involving more than 53,000 men, most of whom were Caucasian and approximately half of whom were circumcised. The authors concluded that being circumcised reduced a man's risk of acquiring H.I.V. by 14%. That finding was statistically nonsignificant, but the authors say it should be regarded as a launching point for future trials. "This study gives us a more complete picture than we've ever had before," says Gregorio Millett, the study's lead author and a senior behavioral scientist at the Centers for Disease Control and Prevention (CDC). "The next step is to design better quality studies to see if there is an association we aren't detecting."

One such question, says Millett, is whether circumcision can reduce infection rates among the subset of men who have only insertive sex with other men, as opposed to those who have only receptive sex or both. Millett's review suggested that among the former group, circumcision lowered H.I.V.-infection risk by 29%, a finding that also showed statistical nonsignificance. But targeting that distinct population in future studies may prove useful for distilling the specific effect of circumcision  and perhaps for future public-health strategies. "For every insertive man who is protected, there might be a receptive man who isn't infected, for the same reason why women get protected...in other words, from a herd-immunity phenomenon," says Dr. Sten Vermund, director of the Institute for Global Health at Vanderbilt University School of Medicine, who co-authored an editorial in the current issue of J.A.M.A.

Circumcision is believed to lower H.I.V. transmission in several ways. The inner surface of the foreskin is rich with cells that are more vulnerable to H.I.V. than cells on other parts of the penis; because they are also closer to the epithelial surface and at higher risk for tears during intercourse, they increase susceptibility to infection. Removal of the foreskin further lowers men's odds of developing genital ulcers (from diseases such as syphilis), which in turn lowers their vulnerability to H.I.V. during intercourse. In theory, circumcision should be protective for all men who participate in insertive sex, including heterosexual men and men who have sex with men.

But researchers note that circumcision is no cure, and no substitute for safe-sex measures such as using condoms. Millett's analysis found that in studies conducted before 1996  before the advent of highly active antiretroviral therapy  circumcision was associated with a statistically significant 53% reduction in H.I.V.-transmission risk, which is on par with the 48% to 60% reduction in infection rates reported by the 2007 trials in Kenya, South Africa and Uganda that studied heterosexual men. After 1996, however, when antiretroviral (ARV) drugs turned H.I.V. into a condition that people lived with rather than died from, the protective effect of circumcision became nonsignificant, Millett found. The widespread belief that ARVs could prevent H.I.V. transmission led to an increase in risky sexual behavior, outbreaks of sexually transmitted infections and increasing rates of H.I.V., which, the study's authors say, may have diminished the relative effectiveness of male circumcision.

"Nobody should frame male circumcision as some sort of panacea," says Vermund. "But it may prove to be one more tool in the toolbox...if you can add it to behavioral risk reduction, prompt diagnosis and access to care, it may be the combination needed to really knock the socks off the H.I.V. epidemic."